1. Field of the Invention
The present invention relates generally to methods and apparatus for treating disorders by cranial nerve stimulation. More particularly, it concerns methods and apparatus for treating reproductive endocrine disorders by vagus nerve stimulation.
2. Description of Related Art
The human nervous system (HNS) includes the brain and the spinal cord, collectively known as the central nervous system (CNS). The central nervous system comprises nerve fibers. The network of nerves in the remaining portions of the human body forms the peripheral nervous system (PNS). Some peripheral nerves, known as cranial nerves, connect directly to the brain to control various brain functions, such as vision, eye movement, hearing, facial movement, and feeling. Another system of peripheral nerves, known as the autonomic nervous system (ANS), controls blood vessel diameter, intestinal movements, and actions of many internal organs. Autonomic functions include blood pressure, body temperature, heartbeat and essentially all the unconscious activities that occur without voluntary control.
Like the rest of the human nervous system, nerve signals travel up and down the peripheral nerves, which link the brain to the rest of the human body. Nerves are typically composed of many individual nerve fibers, which may be of several different types. Some (but not all) nerve fibers in the brain and the peripheral nerves are sheathed in a covering called myelin, which insulates electrical pulses traveling along the nerves. A nerve bundle may comprise up to 100,000 or more individual nerve fibers of different types, including larger diameter A and B fibers which comprise a myelin sheath and C fibers which have a much smaller diameter and are unmyelinated. Different types of nerve fibers, among other things, comprise different sizes, conduction velocities, stimulation thresholds, and myelination status (i.e., myelinated or unmyelinated).
Normal reproductive function depends on complex hormonal communication between the endocrine system and target organs whose functions are regulated by the endocrine system. Normal function is essential to sexual development at puberty and to the cyclic processes of ovulation and menstruation.
The hypothalamus secretes a small peptide, gonadotropin-releasing hormone (GnRH), also known as luteinizing hormone-releasing hormone, which regulates release of the gonadotropins luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from the anterior pituitary gland. LH and FSH promote maturation of gametes and stimulate secretion of sex hormones such as estrogen and testosterone from the gonads. Estrogen and progesterone stimulate various organs of the reproductive system (e.g., breasts, uterus, and vagina) and exert negative and positive feedback effects on the CNS-hypothalamic-pituitary unit, inhibiting and stimulating gonadotropin secretion.
Virtually all hormones are released in short bursts or pulses at intervals of 1 to 3 hr.
LH and FSH are elevated at birth but fall to low levels within a few months and remain low throughout the prepubertal years, with FSH generally slightly higher than LH. The adrenal androgens dehydroepiandrosterone (DHEA) and DHEA sulfate begin to increase several years before puberty. These increases may be important in initiating pubic and axillary hair growth (adrenarche) and other pubertal events.
The mechanisms initiating puberty are not entirely clear. Central influences may inhibit the pulsatile release of GnRH during childhood, then initiate its release to induce puberty early in adolescence. Impairment of these mechanisms may result in delayed puberty.
Variations in hormonal levels are also involved in the menstrual cycle. The follicular (preovulatory) phase of the menstrual cycle extends from the first day of menses to the day before the preovulatory LH surge. During the first half of this phase, FSH secretion is increased slightly, stimulating growth of a cohort of 3 to 30 follicles that have been recruited for accelerated growth during the last days of the preceding cycle. As FSH levels decline, one of the recruited follicles is selected for ovulation; it matures, and the others undergo atresia. Circulating LH levels rise slowly, beginning 1 to 2 days after the increase in FSH. Estrogen and progesterone secretion by the ovaries is relatively constant and remains low early in this phase.
About 7 to 8 days before the LH surge, ovarian secretion of estrogen, particularly of estradiol, by the selected follicle increases slowly at first, then accelerates, generally peaking on the day before the LH surge. The rise in estrogen is accompanied by a slow but steady increase in LH and a decrease in FSH levels. LH and FSH levels may diverge because FSH secretion is preferentially inhibited by estrogens (compared with LH secretion) and is specifically inhibited by inhibin. Just before the LH surge, progesterone levels also begin to increase significantly.
In the ovulatory phase, a series of complex endocrine events culminates in the LH surge—the massive preovulatory release of LH by the pituitary gland. The LH surge results in part from positive estrogen feedback. A smaller increase in FSH secretion occurs simultaneously, but its significance is not understood. As LH levels increase, estradiol levels decrease, but progesterone levels continue to increase. The LH surge typically lasts 36 to 48 hr and consists of multiple large bursts of LH released in pulses. The LH surge, which results in complete maturation of the follicle, is necessary for ovulation—release of the ovum from the mature graafian follicle—which usually occurs 16 to 32 hr after onset of the surge. The mechanism of ovulation is unclear.
During the menstrual cycle, the pulsatile secretion of LH and FSH is determined by the pulsatile secretion of GnRH. The frequency and amplitude of the LH and FSH pulses are modulated by ovarian hormones and vary throughout the menstrual cycle. No separate releasing hormone for FSH has been identified. Evidence suggests that the same cells sometimes contain LH and FSH, so differential release of LH and FSH must result from interactions of various factors (e.g., GnRH, estradiol, inhibin). Also, the disparate half-lives of LH (20 to 30 min) and FSH (2 to 3 hr) affect circulating levels.
Impairment of normal hormonal activity at various stages of the menstrual cycle can result in amenorrhea or infertility, among other ailments. Chronic impairment of normal hormonal activity can result in premature menopause.
Changes in levels of reproductive hormones can also lead to disorders after a person's reproductive years have ended. Reduction in estrogen levels in postmenopausal women can lead to osteoporosis, a weakening of the bones that can lead to a greater incidence of fracture and subsequent decrease in quality of life.